Neuropathic pain management is a major unmet clinical need. Classically used medications, including opioids and non-opioids (primarily NSAIDs), have major side effects associated with their use, and many individuals do not respond to any medications. Neuropathic pain drugs with novel mechanisms of action are being sought as an alternative; however, the only successful FDA-approved drugs, which target calcium channels, have serious limitations to their widespread use. Neurotensin (NT) and its fully active fragment NT(8- 13) have been shown to possess dramatic activity against neuropathic pain when dosed centrally; however, activity is not seen with systemic administration. Halimed Pharmaceuticals has engineered NT(8-13) derivatives that exhibit potent analgesic activity when dosed IV (and, at high concentrations, orally). The compounds are NT-receptor agonists, a novel mechanism of analgesia, thus they may not have the limitations of currently approved medications. We hypothesize that engineered NT(8-13) derivatives can be developed as novel neuropathic pain medications, the foundation of which will be provided by the completion of two Specific Aims in this Phase I application. In Specific Aim 1, 14 highly potent NT(8-13) derivatives will be fully evaluated in the standard Chung model of neuropathic pain with both IV and oral administration. In vitro potency/receptor binding with the two cloned and expressed rat and human NT receptors (NTRs) also will be determined to establish whether there is a correlation with the in vivo results; this would potentially suggest a mechanism of action. The overall stability (degradation t1/2s) of each compound will be determined in simulated intestinal and gastric fluid, plasma, and homogenized brain preparations. This will enable evaluation of whether the relative receptor binding potency and/or one or a combination of half-lives in the different environments is predictive of overall analgesic activity. The three most potent compounds will be advanced into Specific Aim 2, in which their pharmacokinetic/pharmacodynamics properties will be fully characterized. The PK/PD data are crucial for developing the study designs for preclinical toxicity and safety evaluations in animals prediction of effective human dose, and ultimately design of clinical trials. Characterization of three compounds through this Aim will enable flexibility as the program moves forward. Completion of this Aim will provide the foundation needed for preparation of a Phase II application to develop the lead through preclinical studies (synthesis, toxicity, etc.) and IND preparation and submission. This Phase I effort will be performed at Halimed Pharmaceuticals and in collaboration with the PI's long-term collaborator, Dr. Craig Beeson, at the Medical University of South Carolina.